3,3-(disubstituted) cyclohexan-1-ol monomers and related compounds

ABSTRACT

The present invention relates to novel 3,3-(disubstituted)cyclohexan-1-ol monomers and related compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).

This is a continuation of Ser. No. 08/363,123 filed Dec. 23, 1984, and a371 of PCT/US95/16840 filed Dec. 21, 1995.

FIELD OF THE INVENTION

The present invention relates to novel3,3-(disubstituted)cyclohexan-1-ol monomers and related compounds,pharmaceutical compositions containing these compounds, and their use intreating allergic and inflammatory diseases and for inhibiting theproduction of Tumor Necrosis Factor (TNF).

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized byreversible narrowing of the airway and hyperreactivity of therespiratory tract to external stimuli.

Identification of novel therapeutic agents for asthma is made difficultby the fact that multiple mediators are responsible for the developmentof the disease. Thus, it seems unlikely that eliminating the effects ofa single mediator will have a substantial effect on all three componentsof chronic asthma. An alternative to the "mediator approach" is toregulate the activity of the cells responsible for the pathophysiologyof the disease.

One such way is by elevating levels of cAMP (adenosine cyclic3',5'-monophosphate). Cyclic AMP has been shown to be a second messengermediating the biologic responses to a wide range of hormones,neurotransmitters and drugs; Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica, 17-29, 1973!. When theappropriate agonist binds to specific cell surface receptors, adenylatecyclase is activated, which converts Mg⁺² -ATP to cAMP at an acceleratedrate.

Cyclic AMP modulates the activity of most, if not all, of the cells thatcontribute to the pathophysiology of extrinsic (allergic) asthma. Assuch, an elevation of cAMP would produce beneficial effectsincluding: 1) airway smooth muscle relaxation, 2) inhibition of mastcell mediator release, 3) suppression of neutrophil degranulation, 4)inhibition of basophil degranulation, and 5) inhibition of monocyte andmacrophage activation. Hence, compounds that activate adenylate cyclaseor inhibit phosphodiesterase should be effective in suppressing theinappropriate activation of airway smooth muscle and a wide variety ofinflammatory cells. The principal cellular mechanism for theinactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by oneor more of a family of isozymes referred to as cyclic nucleotidephosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotidephosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMPbreakdown in airway smooth muscle and inflammatory cells. Torphy,"Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmaticAgents" in New Drugs for Asthma, Barnes, ed. IBC Technical ServicesLtd., 1989!. Research indicates that inhibition of this enzyme not onlyproduces airway smooth muscle relaxation, but also suppressesdegranulation of mast cells, basophils and neutrophils along withinhibiting the activation of monocytes and neutrophils. Moreover, thebeneficial effects of PDE IV inhibitors are markedly potentiated whenadenylate cyclase activity of target cells is elevated by appropriatehormones or autocoids, as would be the case in vivo. Thus PDE IVinhibitors would be effective in the asthmatic lung, where levels ofprostaglandin E₂ and prostacyclin (activators of adenylate cyclase) areelevated. Such compounds would offer a unique approach toward thepharmacotherapy of bronchial asthma and possess significant therapeuticadvantages over agents currently on the market.

The compounds of this invention also inhibit the production of TumorNecrosis Factor (TNF), a serum glycoprotein. Excessive or unregulatedTNF production has been implicated in mediating or exacerbating a numberof diseases including rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions; sepsis,septic shock, endotoxic shock, gram negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, boneresorption diseases, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC(AIDS related complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis, or pyresis, in addition to a number ofautoimmune diseases, such as multiple sclerosis, autoimmune diabetes andsystemic lupus erythematosis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence ofHIV infection, T-cell-mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after Tcell activation and such virus protein expression and/or replication ismediated or maintained by such T cell activation. Once an activated Tlymphocyte is infected with HIV, the T lymphocyte must continue to bemaintained in an activated state to permit HIV gene expression and/orHIV replication.

Cytokines, specifically TNF, are implicated in activated T-cell-mediatedHIV protein expression and/or virus replication by playing a role inmaintaining T lymphocyte activation. Therefore, interference withcytokine activity such as by inhibition of cytokine production, notablyTNF, in an HIV-infected individual aids in limiting the maintenance of Tcell activation, thereby reducing the progression of HIV infectivity topreviously uninfected cells which results in a slowing or elimination ofthe progression of immune dysfunction caused by HIV infection.Monocytes, macrophages, and related cells, such as kupffer and glialcells, have also been implicated in maintenance of the HIV infection.These cells, like T cells, are targets for viral replication and thelevel of viral replication is dependent upon the activation state of thecells. See Rosenberg et al., The Immunopathogenesis of HIV Infection,Advances in Immunology, Vol. 57, 1989!. Monokines, such as TNF, havebeen shown to activate HIV replication in monocytes and/or macrophagesSee Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990!, therefore,inhibition of monokine production or activity aids in limiting HIVprogression as stated above for T cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalovirus (CMV), influenza virus,adenovirus, and the herpes virus for similar reasons as those noted.

TNF is also associated with yeast and fungal infections. SpecificallyCandida albicans has been shown to induce TNF production in vitro inhuman monocytes and natural killer cells. See Riipi et al., Infectionand Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal ofInfectious Diseases, 164:389-95, 1991. See also Wasan et al.,Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Lukeet al., Journal of Infectious Diseases, 162:211-214, 1990!.

The ability to control the adverse effects of TNF is furthered by theuse of the compounds which inhibit TNF in mammals who are in need ofsuch use. There remains a need for compounds which are useful intreating TNF-mediated disease states which are exacerbated or caused bythe excessive and/or unregulated production of TNF.

SUMMARY OF THE INVENTION

In a first aspect this invention relates to compounds of Formula (I):##STR1## wherein: R₁ is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄R₅)_(n) C(O)NR₄ (CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or--(CR₄ R₅)_(r) R₆ wherein the alkyl moieties unsubstituted orsubstituted with one or more halogens;

m is 0 to 2;

n is 0to4;

r is 0to6;

R₄ and R₅ are independently selected hydrogen or C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted arylaryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl indanyl, indenyl,C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl,C₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted orsubstituted by 1 to 3 methyl groups, one ethyl group, or an hydroxylgroup;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in --(CR₄ R₅)_(n)O(CR₄ R₅)_(m) R₆ ;

X is YR₂, fluorine, NR₄ R₅, or formyl amine;

Y is O or S(O)_(m') ;

m' is 0, 1, or2;

X₂ is O or NR₈ ;

X₃ is hydrogen or X;

X₄ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈ R₈, or NR₈ R₈ ;

R₂ is independently selected from --CH₃ or --CH₂ CH₃ optionallysubstituted by 1 or more halogens;

s is 0 to 4;

W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynylof 2 to 6 carbon atoms;

R₃ is COOR₁₄, C(O)NR₄ R₁₄ or R₇ ;

Z is OR₁₄, OR₁₅, SR₁₄, S(O)_(m') R₇, S(O)₂ NR₁₀ R₁₄, NR₁₀ R₁₄, NR₁₄C(O)R₉, NR₁₀ C(Y')R₁₄, NR₁₀ C(O)OR₇, NR₁₀ C(Y')NR₁₀ R₁₄, NR₁₀ S(O)₂ NR₁₀R₁₄, NR₁₀ C(NCN)NR₁₀ R₁₄, NR₁₀ S(O)₂ R₇, NR₁₀ C(CR₄ NO₂)NR₁₀ R₁₄, NR₁₀C(NCN)SR₉, NR₁₀ C(CR₄ NO₂)SR₉, NR₁₀ C(NR₁₀)NR₁₀ R₁₄, NR₁₀ C(O)C(O)NR₁₀R₁₄, or NR₁₀ C(O)C(O)OR₁₄ ;

Y' is O or S;

R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is unsubstituted or substituted one or more times by methyl orethyl unsubstituted or substituted by 1-3 fluorines, --F, --Br, --Cl,--NO₂, --NR₁₀ R₁₁, --C(O)R₈, --CO₂ R₈, --O(CH₂)₂₋₄ OR₈, --O(CH₂)₂₋₄ OR₈,--O(CH₂)_(q) R₈, --CN, --C(O)NR₁₀ R₁₁, --O(CH₂)_(q) C(O)NR₁₀ R₁₁,--O(CH₂)_(q) C(O)R₉, --NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀ C(O)R₁₁, --NR₁₀C(O)OR₉, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀ R₁₁,--C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂ R₉,--S(O)_(m') R₉, --NR₁₀ C(O)C(O)NR₁₀ R₁₁, --NR₁₀ C(O)C(O)R₁₀, or R₁₃ ;

q is 0, 1, or 2;

R₁₂ is R₁₃, C₃ -C₇ cycloalkyl, or an unsubstituted or substituted arylor heteroaryl group selected from the group consisting of (2-, 3- or4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl,piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl),quinolinyl, naphthyl, and phenyl;

R₈ is independently selected from hydrogen or R₉ ;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁ ;

R₁₁ is hydrogen, or C₁₋₄ alkyl unsubstituted or substituted by one tothree fluorines; or when R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may togetherwith the nitrogen form a 5 to 7 membered ring comprised of carbon orcarbon and one or more additional heteroatoms selected from O, N, or S;

R₁₃ is a substituted or unsubstituted heteroaryl group selected from thegroup consisting of oxazolidinyl, oxazolyl, thiazolyl pyrazolyl,triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl,isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R₁₃ is substitutedon R₁₂ or R₁₃ the rings are connected through a carbon atom and eachsecond R₁₃ ring may be unsubstituted or substituted by one or two C₁₋₂alkyl groups unsubstituted or substituted on the methyl with 1 to 3fluoro atoms;

R₁₄ is hydrogen or R₇ ; or when R₈ and R₁₄ are as NR₈ R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring comprised ofcarbon or carbon and one or more additional heteroatoms selected from O,N, or S;

R₁₅ is C(O)R₁₄, C(O)NR₈ R₁₄, S(O)_(q) NR₈ R₁₄ or S(O)_(q) R₇ where q is0, 1 or 2;

provided that:

(f) R₇ is not C₁₋₄ alkyl unsubstituted or substituted by one to threefluorines;

or the pharmaceutically acceptable salts thereof.

This invention also relates to the pharmaceutical compositionscomprising a compound of Formula (I) and a pharmaceutically acceptablecarrier or diluent.

The invention also relates to a method of mediation or inhibition of theenzymatic activity (or catalytic activity) of PDE IV in mammals,including humans, which comprises administering to a mammal in needthereof an effective amount of a compound of Formula (I) as shown below.

The invention further provides a method for the treatment of allergicand inflammatory disease which comprises administering to a mammal,including humans, in need thereof, an effective amount of a compound ofFormula (I).

The invention also provides a method for the treatment of asthma whichcomprises administering to a mammal, including humans, in need thereof,an effective amount of a compound of Formula (I).

This invention also relates to a method of inhibiting TNF production ina mammal, including humans, which method comprises administering to amammal in need of such treatment, an effective TNF inhibiting amount ofa compound of Formula (I). This method may be used for the prophylactictreatment or prevention of certain TNF mediated disease states amenablethereto.

This invention also relates to a method of treating a human afflictedwith a human immunodeficiency virus (HIV), which comprises administeringto such human an effective TNF inhibiting amount of a compound ofFormula (I).

Compounds of Formula (I) are also useful in the treatment of additionalviral infections, where such viruses are sensitive to upregulation byTNF or will elicit TNF production in vivo.

In addition, compounds of Formula (I) are also useful in treating yeastand fungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo.

DETAILED DESCRIPTION OF THE INVENTION

This invention also relates to a method of mediating or inhibiting theenzymatic activity (or catalytic activity) of PDE IV in a mammal in needthereof and to inhibiting the production of TNF in a mammal in needthereof, which comprises administering to said mammal an effectiveamount of a compound of Formula (I).

Phosphodiesterase IV inhibitors are useful in the treatment of a varietyof allergic and inflammatory diseases including: asthma, chronicbronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma,psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis,Crohn's disease, reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock and adult respiratory distresssyndrome. In addition, PDE IV inhibitors are useful in the treatment ofdiabetes insipidus and central nervous system disorders such asdepression and multi-infarct dementia.

The viruses contemplated for treatment herein are those that produce TNFas a result of infection, or those which are sensitive to inhibition,such as by decreased replication, directly or indirectly, by the TNFinhibitors of Formula (I). Such viruses include, but are not limited toHIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus andthe Herpes group of viruses, such as, but not limited to, Herpes zosterand Herpes simplex.

This invention more specifically relates to a method of treating amammal, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of Formula (I).

The compounds of this invention may also be used in association with theveterinary treatment of animals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to feline immunodeficiencyvirus (FIV) or other retroviral infection such as equine infectiousanemia virus, caprine arthritis virus, visna virus, maedi virus andother lentiviruses.

The compounds of this invention are also useful in treating yeast andfungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo. A preferreddisease state for treatment is fungal meningitis. Additionally, thecompounds of Formula (I) may be administered in conjunction with otherdrugs of choice for systemic yeast and fungal infections. Drugs ofchoice for fungal infections, include but are not limited to the classof compounds called the polymixins, such as Polymycin B, the class ofcompounds called the imidazoles, such as clotrimazole, econazole,miconazole, and ketoconazole; the class of compounds called thetriazoles, such as fluconazole, and itranazole, and the class ofcompound called the Amphotericins, in particular Amphotericin B andliposomal Amphotericin B.

The compounds of Formula (I) may also be used for inhibiting and/orreducing the toxicity of an anti-fungal, anti-bacterial or anti-viralagent by administering an effective amount of a compound of Formula (I)to a mammal in need of such treatment. Preferably, a compound of Formula(I) is administered for inhibiting or reducing the toxicity of theAmphotericin class of compounds, in particular Amphotericin B.

The term "C₁₋₃ alkyl", "C₁₋₄ alkyl", "C₁₋₆ alkyl" or "alkyl" groups asused herein is meant to include both straight or branched chain radicalsof 1 to 10, unless the chain length is limited thereto, including, butnot limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, and the like.

"Alkenyl" means both straight or branched chain radicals of 1 to 6carbon lengths, unless the chain length is limited thereto, includingbut not limited to vinyl, 1-propenyl, 2-propenyl, 2-propynyl, or3-methyl-2-propenyl.

The term "cycloalkyl" or "cycloalkyl alkyl" means groups of 3-7 carbonatoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, orcyclohexyl.

"Aryl" or "aralkyl", unless specified otherwise, means an aromatic ringor ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl,or naphthyl. Preferably the aryl is monocyclic, ire, phenyl. The alkylchain is meant to include both straight or branched chain radicals of 1to 4 carbon atoms. "Heteroaryl" means an aromatic ring system containingone or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl,pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl.

"Halo" means all halogens, i.e., chloro, fluoro, bromo, or iodo.

"Inhibiting the production of IL-1" or "inhibiting the production ofTNF" means:

a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, ina human to normal levels or below normal levels by inhibition of the invivo release of IL-1 by all cells, including but not limited tomonocytes or macrophages;

b) a down regulation, at the translational or transcriptional level, ofexcessive in vivo IL-1 or TNF levels, respectively, in a human to normallevels or below normal levels; or

c) a down regulation, by inhibition of the direct synthesis of IL-1 orTNF levels as a postranslational event.

The phrase "TNF mediated disease or disease states" means any and alldisease states in which TNF plays a role, either by production of TNFitself, or by TNF causing another cytokine to be released, such as butnot limited to IL-1 or IL-6. A disease state in which IL-1, for instanceis a major component, and whose production or action, is exacerbated orsecreted in response to TNF, would therefore be considered a diseasestate mediated by TNF. As TNF-β (also known as lymphotoxin) has closestructural homology with TNF-α (also known as cachectin), and since eachinduces similar biologic responses and binds to the same cellularreceptor, both TNF-α and TNF-β are inhibited by the compounds of thepresent invention and thus are herein referred to collectively as "TNF"unless specifically delineated otherwise. Preferably TNF-α is inhibited.

"Cytokine" means any secreted polypeptide that affects the functions ofcells, and is a molecule which modulates interactions between cells inimmune, inflammatory, or hematopoietic responses. A cytokine includes,but is not limited to, monokines and lymphokines regardless of whichcells produce them.

The cytokine inhibited by the present invention for use in the treatmentof a HIV-infected human must be a cytokine which is implicated in (a)the initiation and/or maintenance of T cell activation and/or activatedT cell-mediated HIV gene expression and/or replication, and/or (b) anycytokine-mediated disease associated problem such as cachexia or muscledegeneration. Preferrably, his cytokine is TNF-α.

All of the compounds of Formula (I) are useful in the method ofinhibiting the production of TNF, preferably by macrophages, monocytesor macrophages and monocytes, in a mammal, including humans, in needthereof. All of the compounds of Formula (I) are useful in the method ofinhibiting or mediating the enzymatic or catalytic activity of PDE IVand in treatment of disease states mediated thereby.

Preferred compounds are as follows:

When R₁ is an alkyl substituted by 1 or more halogens, the halogens arepreferably fluorine and chlorine, more preferably a C₁₋₄ alkylsubstituted by 1 or more fluorines. The preferred halo-substituted alkylchain length is one or two carbons, and most preferred are the moieties--CF₃, --CH₂ F, --CHF₂, --CF₂ CHF₂, --CH₂ CF₃, and --CH₂ CHF₂. PreferredR₁ substitutents for the compounds of Formula (I) are CH₂ -cyclopropylCH₂ -C₅₋₆ cycloalkyl, C₄₋₆ cycloalkyl unsubstituted or substituted withOH, C₇₋₁₁ polycycloalkyl, (3- or 4-cyclopentenyl), phenyl,tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkyl unsubstituted or substitutedby 1 or more fluorines, --(CH₂)₁₋₃ C(O)O(CH₂)₀₋₂ CH₃, --(CH₂)₁₋₃O(CH₂)₀₋₂ CH₃, and --(CH₂)₂₋₄ OH.

When R₁ term contains the moiety (CR₄ R₅), the R₄ and R₅ terms areindependently hydrogen or alkyl. This allows for branching of theindividual methylene units as (CR₄ R₅)_(n) or (CR₄ R₅)_(m) ; eachrepeating methylene unit is independent of the other, e.g., (CR₄ R₅)_(n)wherein n is 2 can be --CH₂ CH(--CH₃)--, for instance. The individualhydrogen atoms of the repeating methylene unit or the branchinghydrocarbon can unsubstituted or be substituted by fluorine independentof each other to yield, for instance, the preferred R₁ substitutions, asnoted above.

When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo 2.2.1!-heptyl,bicyclo 2.2.2!octyl, bicyclo 3.2.1!octyl, tricyclo 5.2.1.0²,6 !decyl,etc. additional examples of which are described in Saccamano et al., WO87/06576, published 5 Nov. 1987.

W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, andwhere it is alkenyl or alkynyl, that one or two double or triple bondsbe present. It is most preferred that W is ethynyl or 1,3-butadiynyl.

Z is preferably OR₁₄, OR₁₅, SR₁₄, S(O)_(m') R₇, S(O)₂ NR₁₀ R14, NR₁₀R₁₄, NR₁₄ C(O)R₉, NR₁₀ C(O)R₁₄, NR₁₀ C(O)OR₇, NR₁₀ C(O)NR₁₀ R₁₄, NR₁₀S(O)₂ NR₁₀ R₁₄, NR₁₀ C(NCN)NR₁₀ R₁₄, NR₁₀ S(O)₂ R₇, NR₁₀ C(CR₄ NO₂)NR₁₀R₁₄, NR₁₀ C(NCN)SR₉, NR₁₀ C(CR₄ NO₂)SR₉, NR₁₀ C(NR₁₀)NR₁₀ R₁₄, NR₁₀C(O)C(O)NR₁₀ R₁₄, or NR₁₀ C(O)C(O)OR₁₄.

Preferred X groups for Formula (I) are those wherein X is YR₂ and Y isoxygen. The preferred X₂ group for Formula (I) is that wherein X₂ isoxygen. The preferred X₃ group for Formula (I) is that wherein X₃ ishydrogen. Preferred R₂ groups, where applicable, is a C₁₋₂ alkylunsubstituted or substituted by 1 or more halogens. The halogen atomsare preferably fluorine and chlorine, more preferably fluorine. Morepreferred R₂ groups are those wherein R₂ is methyl, or thefluoro-substituted alkyls, specifically a C₁₋₂ alkyl, such as a --CF₃,--CHF₂, or --CH₂ CHF₂ moiety. Most preferred are the --CHF₂ and --CH₃moieties.

R₃ is COOR₁₄, C(O)NR₄ R₁₄ or R₇.

Preferred R₇ moieties include unsubstituted or substituted by --(CH₂)₁₋₂(cyclopropyl), --(CH₂)₀₋₂ (cyclobutyl), --(CH₂)₀₋₂ (cyclopentyl),--(CH₂)₀₋₂ (cyclohexyl), --(CH₂)₀₋₂ (2-, 3- or 4-pyridyl), (CH₂)₁₋₂(2-imidazolyl), (CH₂)₂ (4-morpholinyl), (CH₂)₂ (4-piperazinyl), (CH₂)₁₋₂(2-thienyl), (CH₂)₁₋₂ (4-thiazolyl), and (CH₂)₀₋₂ phenyl.

Preferred rings when R₁₀ and R₁₁ in the moiety --NR₁₀ R₁₁ together withthe nitrogen to which they are attached form a 5 to 7 membered ringcomprised of carbon or carbon and at least one heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl,2-(R₈)-1-imidazolyl, 1-pyrazolyl, 3-(R₈)-1-pyrazolyl, 1-triazolyl,2-triazolyl, 5-(R₈)-1-triazolyl, 5-(R₈)-2-triazolyl,5-(R₈)-1-tetrazolyl, 5-(R₈)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl,morpholinyl, piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R₁₀ and R₁₄ in the moiety --NR₁₀ R₁₄ together withthe nitrogen to which they are attached may form a 5 to 7 membered ringcomprised of carbon or carbon and at least one heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl,1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl,piperazinyl, and pyrrolyl. The respective rings may be additionallysubstituted, where applicable, on an available nitrogen or carbon by themoiety R₇ as described herein for Formula (I). Illustrations of suchcarbon substitutions includes, but is not limited to,2-(R₇)-1-imidazolyl, 4-(R₇)-1-imidazolyl, 5-(R₇)-1-imidazolyl,3-(R₇)-1-pyrazolyl, 4-(R₇)-1-pyrazolyl, 5-(R₇)-1-pyrazolyl,4-(R₇)-2-triazolyl, 5-(R₇)-2-triazolyl, 4-(R₇)-1-triazolyl,5-(R₇)-1-triazolyl, 5-(R₇)-1-tetrazolyl, and 5-(R₇)-2-tetrazolyl.Applicable nitrogen substitution by R₇ includes, but is not limited to,1-(R₇)-2-tetrazolyl, 2-(R₇)-1-tetrazolyl, 4-(R₇)-1-piperazinyl. Whereapplicable, the ring may be substituted one or more times by R₇.

Preferred groups for NR₁₀ R₁₄ which contain a heterocyclic ring are5-(R₁₄)-1-tetrazolyl, 2-(R₁₄)-1-imidazolyl, 5-(R₁₄)-2-tetrazolyl,4-(R₁₄)-1-piperazinyl, or 4-(R₁₅)-1-piperazinyl.

Preferred rings for R₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl 1,2,3!), (3- or 5-triazolyl 1,2,4!),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl 1,2,4!), (2-oxadiazolyl 1,3,4!), (2-thiadiazolyl 1,3,4!),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

When the R₇ group is unsubstituted or substituted by a heterocyclic ringsuch as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, theheterocyclic ring itself may be unsubstituted or substituted by R₈either on an available nitrogen or carbon atom, such as1-(R₈)-2-imidazolyl, 1-(R₈)-4-imidazolyl, 1-(R₈)-5-imidazolyl,1-(R₈)-3-pyrazolyl, 1-(R₈)-4-pyrazolyl, 1-(R₈)-5-pyrazolyl,1-(R₈)-4-triazolyl, or 1-(R₈)-5-triazolyl. Where applicable, the ringmay be substituted one or more times by R₈.

Preferred are those compounds of Formula (I) wherein R₁ is --CH₂-cyclopropyl, --CH₂ -C₅₋₆ cycloalkyl, --C₄₋₆ cycloalkyl unsubstituted orsubstituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzylor --C₁₋₂ alkyl unsubstituted or substituted by 1 or more fluorines, and--(CH₂)₂₋₄ OH, R₂ is methyl or fluoro-substituted alkyl, W is ethynyl or1,3-butadiynyl; R₃ is R₇ where R₇ is an unsubstituted or substitutedaryl or heteroaryl ring, X is YR₂, and Z is OR₁₄, OR₁₅, NR₁₀ R₁₄, orNR₁₄ C(O)R₉.

Most preferred are those compounds wherein R₁ is --CH₂ -cyclopropyl,cyclopentyl, 3-hydroxycyclopentyl, methyl or CF₂ H; X is YR₂ ; Y isoxygen; X₂ is oxygen; X₃ is hydrogen; and R₂ is CF₂ H or methyl, W isethynyl or 1,3-butadiynyl, and R₃ is a substituted or unsubstitutedpyrimidinyl ring.

It will be recognized that some of the compounds of Formula (I) mayexist in both racemic and optically active forms; some may also exist indistinct diastereomeric forms possessing distinct physical andbiological properties. All of these compounds are considered to bewithin the scope of the present invention.

Pharmaceutically acceptable salts of the instant compounds, where theycan be prepared, are also intended to be covered by this invention.These salts will be ones which are acceptable in their application to apharmaceutical use. By that it is meant that the salt will retain thebiological activity of the parent compound and the salt will not haveuntoward or deleterious effects in its application and use in treatingdiseases.

Pharmaceutically acceptable salts are prepared in a standard manner. Theparent compound, dissolved in a suitable solvent, is treated with anexcess of an organic or inorganic acid, in the case of acid additionsalts of a base, or an excess of organic or inorganic base where themolecule contains a COOH for example.

Pharmaceutical compositions of the present invention comprise apharmaceutical carrier or diluent and some amount of a compound of theformula (I). The compound may be present in an amount to effect aphysiological response, or it may be present in a lesser amount suchthat the user will need to take two or more units of the composition toeffect the treatment intended. These compositions may be made up as asolid, liquid or in a gaseous form. Or one of these three forms may betransformed to another at the time of being administered such as when asolid is delivered by aerosol means, or when a liquid is delivered as aspray or aerosol.

The nature of the composition and the pharmaceutical carrier or diluentwill, of course, depend upon the intended route of administration, forexample parenterally, topically, orally or by inhalation.

For topical administration the pharmaceutical composition will be in theform of a cream, ointment, liniment, lotion, pastes, aerosols, and dropssuitable for administration to the skin, eye, ear, or nose.

For parenteral administration the pharmaceutical composition will be inthe form of a sterile injectable liquid such as an ampule or an aqueousor non-aqueous liquid suspension.

For oral administration the pharmaceutical composition will be in theform of a tablet, capsule, powder, pellet, atroche, lozenge, syrup,liquid, or emulsion.

When the pharmaceutical composition is employed in the form of asolution or suspension, examples of appropriate pharmaceutical carriersor diluents include: for aqueous systems, water, for non-aqueoussystems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil,peanut oil, sesame oil, liquid parafins and mixtures thereof with water;for solid systems, lactose, kaolin and mannitol; and for aerosolsystems, dichlorodifluoromethane, chlorotrifluoroethane and compressedcarbon dioxide. Also, in addition to the pharmaceutical carrier ordiluent, the instant compositions may include other ingredients such asstabilizers, antioxidants, preservatives, lubricants, suspending agents,viscosity modifiers and the like, provided that the additionalingredients do not have a detrimental effect on the therapeutic actionof the instant compositions.

The pharmaceutical preparations thus described are made following theconventional techniques of the pharmaceutical chemist as appropriate tothe desired end product.

In these compositions, the amount of carrier or diluent will vary butpreferably will be the major proportion of a suspension or solution ofthe active ingredient. When the diluent is a solid it may be present inlesser, equal or greater amounts than the solid active ingredient.

Usually a compound of formula I is administered to a subject in acomposition comprising a nontoxic amount sufficient to produce aninhibition of the symptoms of a disease in which leukotrienes are afactor. Topical formulations will contain between about 0.01 to 5.0% byweight of the active ingredient and will be applied as required as apreventative or curative agent to the affected area. When employed as anoral, or other ingested or injected regimen, the dosage of thecomposition is selected from the range of from 50 mg to 1000 mg ofactive ingredient for each administration. For convenience, equal doseswill be administered 1 to 5 times daily with the daily dosage regimenbeing selected from about 50 mg to about 5000 mg.

No unacceptable toxicological effects are expected when these compoundsare administered in accordance with the present invention.

Methods of Preparation

Synthetic Scheme(s) With Textual Description

Preparing compounds of Formula (I) can be carried out by one of skill inthe art according to the procedures outlined in the Examples, infra. Thepreparation of any remaining compounds of Formula (I) not describedtherein may be prepared by the analogous processes disclosed hereinwhich comprise:

Compounds of Formula (I) may be prepared by the processes disclosedherein which comprise reacting a terminal acetylene, wherein Zrepresents Z as defined in relation to Formula (I) or a groupconvertible to Z, as, e.g., compound 1-Scheme 1, with an appropriatehalide, R₃ X, wherein R₃ represents R₃ as defined in relation to Formula(I) or a group convertible to R₃, in the presence of a suitablecatalyst, such as a copper (I) halide and a bivalent or zerovalentpalladium compound in the presence of, e.g., triphenylphosphine, in asuitable solvent, such as an amine, as in the procedure of Brandsma etal. (Syn. Comm., 1990, 20, 1889), provides a compound of the Formula2-Scheme 1.

For compounds wherein X or X₃ is other than Br, I, NO₂, amino, orS(O)_(m') R₂ when m' is 0, 1 or 2 and wherein Z is OH, reacting acompound of Formula (2) ##STR2## wherein R₁ represents R₁ as defined inrelation to Formula (I) or a group convertable to R₁ and X and X₃represent X and X₃ as defined in relation to Formula (I) or a groupconvertable to X or X₃ and R₃ is an acetylinic group, with a suitablereducing agent, such as lithium borohydride, disiamylborane, lithiumaluminum tris-(t-butoxide), or sodium borohydride, in a suitablenon-reacting solvent, such as 1,2-dimethoxyethane, tetrahydrofuran or analcohol, to provide compounds of Formula (I) wherein Z is OH;preparation of such compounds of Formula (I) proceed in an analogousfashion from the compound of Formula (2) wherein ═Z' is an aldehydeprotecting group, such as a dimethylacetal or a dioxolane, followed bydeprotection to the aldehyde and subsequent elaboration by standardprocedures known to those of skill in the art to the remaining compoundsof Formula (I) wherein Z' is other than O.

For compounds wherein Z is NH₂, NHCH₃, or N(CH₃)₂, reacting a compoundof Formula (2) wherein R₁ represents R₁ as defined in relation toFormula (I) or a group convertable to R₁ and X and X₃ represent X and X₃as defined in relation to Formula (I) or a group convertable to X or X₃with an ammonium salt, such as, for example, ammonium formate,methylamine hydrochloride, or dimethylamine hydrochloride, respectively,in the presence of a suitable reducing agent, such as sodiumcyanoborohydride, in a suitable solvent, such as an alcohol, to providecompounds of Formula (I) wherein Z is NH₂, NHCH₃, or N(CH₃)₂,respectively.

Alternatively, compounds of Formula (I) wherein Z is NH₂ may be preparedby reacting an appropriate alcohol of Formula (2) wherein Z is OH, R₁represents R₁ as defined in relation to Formula (I) or a groupconvertable to R₁ and X and X₃ represent X and X₃ as defined in relationto Formula (I) or a group convertable to X or X₃ with a complex of aphosphine, such as triphenyl phosphine, and an azodicarboxylate ester inthe presence of an imide, such as phthalimide, followed by, e.g.,hydrazinolysis in an alcoholic solvent.

Compounds of Formula (I) wherein Z is SR₁₄ may be prepared by reactingan appropriate compound of Formula (2) wherein Z is a leaving group,e.g., a mesylate, tosylate, chloride, or bromide, R₁ represents R₁ asdefined in relation to Formula (I) or a group convertable to R₁ and Xand X₃ represent X and X₃ as defined in relation to Formula (I) or agroup convertable to X or X₃ with a metal salt of a mercaptan, such asNaSR₁₄ in an appropriate aprotic solvent. Compounds of Formula (I)wherein Z is SH may be prepared by reacting an appropriate alcohol ofFormula (2) wherein Z is OH with a complex of a phosphine, such astriphenyl phosphine, and an azodicarboxylate ester in the presence ofthiolacetic acid, followed by hydrolysis of the resulting thiolacetate.

Compounds of Formula (I) wherein Z is OH may be interconverted using thestandard alcohol inversion procedures known in the art. It will berecognized that compounds of Formula (I) may exist in two distinctdiastereomeric forms possessing distinct physical and biologicalproperties; such isomers may be separated by standard chromatographicmethods. Such isomers may be independently converted to the remainingcompounds of Formula (I) wherein Z is other than OH, SH, and NH₂ by anyof the wide variety of O, S, and N alkylation, sulfamidation, imidation,oxidation, or acylation procedures known to those of skill in the art.

For example, with proper manipulation of any chemically sensitivefunctional groups, compounds of Formula (1) wherein NR₁₃ R₁₄ represent aring, such as a 1- or 2-tetrazole, may be derived from reaction of anappropriate compound of Formula (I) wherein Z is a leaving group, e.g.,a mesylate, tosylate, chloride or bromide, with the appropriate metalsalt of HNR₁₃ R₁₄, e.g., 5-(R₁₄)-tetrazole; the appropriate compound ofFormula (I) wherein Z is mesylate, tosylate, Br or Cl, derived in turnfrom the appropriate compound of Formula (1) wherein Z is OH.

With proper manipulation (protection/deprotection) of any chemicallysensitive functional groups:

a) Compounds of the Formula (I) wherein X or X₃ are formyl amine may beformed at the last step, by formylating a compound wherein X or X₃ isNH₂, obtained by removal of a protecting group from the aminefunctionality; such protective groups are well known to those skilled inthe art, See Greene, T. and Wuts, P. G. M., Protecting Groups in OrganicSynthesis, 2nd Ed., John Wiley and Sons, New York (1991).

b) Compounds of the Formula (I) wherein X or X₃ are Br, I or SR₂ may beprepared from a similarly deprotected amine by diazotization of theamine and diazonium displacement.

c) Compounds of the Formula (I) wherein X or X₃ are NO₂ may be preparedfrom a similarly deprotected amine by oxidation of the amine to thenitro group.

Compounds of Formula 1-Scheme 1 may be prepared by procedures analogousto those described above, as further recited in U.S. patent applicationSer. No. 08/131,053 and its progeny. ##STR3##

Alternatively, compounds of the Formula (I), wherein Z and R₃ representZ and R₃ as defined in relation to Formula (I) or a group convertible toZ or R₃, may be prepared from the corresponding ketones as, e.g.,compound 1-Scheme 2, by the synthetic procedures described belowutilizing certain cyclohexan-3-one intermediates and as described inU.S. patent application Ser. No. 08/131,053 and its progeny.

Compounds of Formula (I) may be prepared from precursors where Z is O bystarting with compounds of Formula (I) which have an CHO at the 1position on the cyclohexane ring and at position 3 a carbonyl groupwhich is protected in the form of a ketal protecting group by reactingthe carbonyl compound with a mixture of dimethyl(diazomethyl)phosphonate and potassium t-butoxide or other suitablebase, in an inert solvent, such as tetrahydrofuran, at reducedtemperature, followed by appropriate workup and ketone deprotection.This provides compounds of Formula (I) which have a C.tbd.CH.Alternatively, prior to ketone deprotection, alkylation of the acetyleneunder the appropriate conditions with a strong base followed by analkylating agent, R₃ L, wherein L is a leaving group followed by ketonedeprotection, provides compounds of Formula (I) which have the C.tbd.CR₃group.

Intermediates wherein X or X₃ is formyl amine and Z is O may be preparedby formylating, at the last step, a compound wherein ═Z is a protectedketone and X is NH₂, obtained by removal of a protecting group from theamine functionality; such protective groups are well known to thoseskilled in the art, See Greene, T. and Wuts, P. G. M., Protecting Groupsin Organic Synthesis, 2nd Ed, John Wiley and Sons, New York (1991).

c) Intermediates wherein X or X₃ is Br or I and Z is O may be preparedfrom a similarly deprotected amine by diazotization of the amine anddiazonium displacement via Sandmeyer reaction.

d) Intermediates wherein X or X₃ is NO₂ and Z is O may be prepared froma similarly deprotected amine by oxidation of the amine to the nitrogroup.

e) Intermediates wherein Y is S(O)m' when m' is 1 or 2 and Z is O may beprepared from those intermediates where Y is S by oxidation of the SR₂moiety under conditions well known to those skilled in the art.

Converting the ketones to the alcohols, or other Z groups as definedherein above is carried out by the following Schene 2 ##STR4##

Alternatively, oxidative carbonylation of a terminal acetylene as, e.g.,compound 1-Scheme 3, using an appropriate metal salt, such as a coppersalt with a catalytic amount of a palladium salt, in the presence of asuitable base as an acid trap, such as sodium acetate, in a suitablealcohol, such as methanol, as in the method of Tsuji et al. (Tet. Lett.,1980, 21, 849), then provides the compound of the Formula 2-Scheme 3below; such compounds may then be converted to other compounds of theFormula (I) by manipulation of the ketone as described above and byindependent manipulation of the carboxylic ester moiety using standardtransesterification or amidation conditions. Syntheses of such ketonestarting materials are also described in PCT application PCT/US94/10815filed 23 Sep. 1994 wherein is described the following procedure:

For internmediates where X and X₃ are other than Br, I, NO₂, amine,formyl amine, or S(O)m' when m' is 1 or 2, reacting a compound ofFormula (2) ##STR5## wherein R₁ represents R₁ as defined in relation toFormula (I) or a group convertable to R₁ and X represents X as definedin relation to Formula (I) or a group convertable to X and X₃ representsX₃ as defined in relation to Formula (I) or a group convertable to X₃and X₄ is a counter ion (e.g., lithium, magnesium, etc.) with a compoundof the Formula (3) ##STR6## wherein X₅ is, e.g., OCH₃, OC₂ H₅,OCH(CH₃)₂, etc., followed by appropriate workup to provide a compound ofthe Formula (4) ##STR7## wherein R₁ represents R₁ as defined in relationto Formula (I) or a group convertable to R₁ and X represents X asdefined in relation to Formula (I) or a group convertable to X and X₃represents X₃ as defined in relation to Formula (I) or a groupconvertable to X₃ (see the patent application WO 9115-451-A published byWIPO). Michael-type reaction of such a compound of the Formula (4) withthe appropriate precursor of R₃ then provides a compound of the Formula(1); for example, use of diethylaluminum cyanide provides a compound ofthe Formula (1) wherein R₁ represents R₁ as defined in relation toFormula (I) or a group convertable to R₁ and X represents X as definedin relation to Formula (I) or a group convertable to X and X₃ representsX₃ as defined in relation to Formula (I) or a group convertable to X₃and R₃ is CN.

Intermediates wherein the 3-position radical is CHO and Z is O may beprepared from other intermediates in which the 3-position is CN and Z isO after appropriate protection of the ketone as, e.g., a ketal. Thosecompounds are then under go reduction of the CN moiety with, e.g.,di-isobutylaluminum hydride, followed by appropriate workup.

Using in the method of Tsuji et al. (Tet. Lett., 1980, 21, 849), andtreating the acetylenic intermediate of Formula 2-Scheme 3 below;intermediates may then be converted to compounds of Formula (I) bymanipulation of the ketone as described above and by independentmanipulation of the carboxylic ester moiety using standardtransesterification or amidation conditions. ##STR8##

Likewise, oxidative carbonylation of a terminal acetylene as, e.g.,compound 1-Scheme 4, wherein Z represents Z as defined in relation toFormula (I) or a group convertible to Z, using an appropriate metalsalt, such as a copper salt with a catalytic amount of a palladium salt,in the presence of a suitable base as an acid trap, such as sodiumacetate, in a suitable alcohol, such as methanol, as in the method ofTsuji et al. (Tet. Lett., 1980, 21, 849), then provides the compound ofthe Formula 2-Scheme 4; such compounds may then be converted to othercompounds of the Formula (I) by manipulation of the carboxylic estermoiety using standard transesterification or amidation conditions.##STR9##

Compounds where Z is a group other than --OH can be prepared by methodsknown in the art and in particular by manipulation of the --OH. Suchmethods are described in copending U.S. application Ser. No. 08/131,053and its progeny PCT application serial number PCT/US94/10798 filed 23Sep. 1994.

Preparation of the remaining compounds of the Formula (I) may beaccomplished by procedures analogous to those described above and in theExamples, infra.

It will be recognized that some compounds of the Formula (I) may existin distinct diastereomeric forms possessing distinct physical andbiological properties; such isomers may be separated by standardchromatographic methods.

The following examples are given to more fully illustrate the describedinvention. These examples are intented solely for illustrating theinvention and should not be read to limit the invention in any manner.Reference is made to the claims for what is reserved to the inventorshereunder.

Experimentals

EXAMPLE 1 Preparation of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclohexan-1-one

1a) 3-(3-cyclopentlyoxy-4-methoxyphenyl)-3-trimethylsilylethynylcyclohexan-1-one

n-Butyllithium (2.45M in hexanes, 5.7 mL, 13.96 mmol) was added dropwiseover 5 min to a solution of trimethylsilylacetylene (1.97 mL, 13.96mmol) dissolved in dry ether (30 mL) at -45° C. under an argonatmosphere. After 1.5 h, this solution was cannulated into a solution ofdimethylaluminum chloride (1.0M in hexanes, 13.96 mL, 13.96 mmol). After3.5 h at room temperature, the mixture was filtered through Celite®under an argon atmosphere. In a separate flask, diisobutylaluminumhydride (1.0M in toluene, 1.4 mL, 1.4 mmol) was added dropwise to astirred mixture of nickel acetylacetonate (360 mg, 1.4 mmol) in dryether (25 mL) at 0° C. under an argon atmosphere. After 10 min, themixture was further cooled to -10° C. and the solution of aluminumacetylide was added via cannulation over 15 min.3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-2-en-1-one (2.0 g, 6.98mmol, prepared as described in U.S. Pat. No. 5,362,915) dissolved in dryether (70 mL) was added dropwise over 20 min. After 18 h at roomtemperature, the mixture was poured into a 100 mL saturated aqueoussolution of potassium phosphate (monobasic) at 0° C., 100 mL of aqueous3N HCl solution was added and the aqueous layer was extracted twice withether. The combined extract was washed with brine, was dried (magnesiumsulfate) and was evaporated. Purification by flash chromatography,eluting with 2:1 hexanes/ether followed by trituration fromether/hexanes, then furthur purification of the mother liquor by flashchromatography, eluting with 4:1 hexanes/ethyl acetate followed bytrituration from ether/hexanes, provided a white solid. mp 102°-103° C.

1b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclohexan-1-one

A mixture of potassium fluoride (900 mg, 15.6 mmol) and3-(3-cyclopentyloxy-4-methoxyphenyl)-3-trimethylsilylethynylcyclohexan-1-one(0.3 g, 0.78 mmol) were stirred in dry N,N-dimethylformamide (3 mL)under an argon atmosphere. After 18 h, the solvent was removed in vacuo,the residue was partitioned between water and ethyl acetate, the aqueouslayer was extracted twice with ethyl acetate, the combined extract wasdried (magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 4:1 hexanes/ethyl acetate provided a clearcolorless oil. Anal. (C₂₀ H₂₄ O₃.1/10 H₂ O) calcd: C 76.45, H 7.76;found: C 76.32, H 7.60.

EXAMPLE 2 Preparation of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylcyclohexan-1-one

To a solution of the compound of Example 1b (0.125 g, 0.4 mmol) andiodobenzene (0.4 mL, 2.0 mmol) in piperidine (6 mL) under an argonatmosphere was added trace tetrakis(triphenylphosphine)palladium(0),copper(I) iodide and triphenylphosphine. The mixture was refluxed for 5h, then concentrated in vacuo. The residue was diluted with ethylacetate (100 mL), was washed with brine, was dried (MgSO₄) and wasevaporated. Purification by flash chromatography, eluting with 2:1hexanes/ethyl acetate, followed by trituration from ether/hexanes,provided the title compound as white solid (0.09 g, 58%), m.p. 90°-91°C.

EXAMPLE 3 Preparation of trans-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylcyclohexan-1-ol! andcis-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylcyclohexan-1-ol!

The compound from Example 1(b) (0.18 g, 0.46 mmol) was dissolved in 10:1methanol/ethanol (11 mL) with gentle heating under an argon atmosphereand was treated with sodium borohydride (0.035 g, 0.9 mmol). After 0.5h, 10% aqueous NaOH was added and the mixture was concentrated in vacuo.The residue was partitioned between ethyl acetate and water. The organicphase was washed with brine, was dried (MgSO₄) and was evaporated.Purification by flash chromatography, eluting with 4:1 hexanes/ethylacetate, provided the title compounds as colorless oils. The majorproduct: TLC R_(f) 0.26 (silica gel, 3:1 hexanes/ethyl acetate). ¹ H NMR(400 MHz, CDCl₃) δ 7.44 (m, 2H), 7.30 (m, 3H), 7.16 (d, J=2.3 Hz, 1H),7.06 (dd, J=8.4, 2.2 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.80 (m, 1H), 4.1(m, 1H), 3.84 (s, 3H), 2.35-1.60 (m, 16H). The minor product: TLC R_(f)0.20 (silica gel, 3:1 hexanes/ethyl acetate). ¹ H NMR (400 MHz, CDCl₃) δ7.44 (m, 2H), 7.31 (m, 3H), 7.25 (br s, 1H), 7.12 (m, 1H), 6.86 (d,J=8.5 Hz, 1H), 4.81 (m, 1H), 4.24 (m, 1H), 3.86 (s ,3H), 2.35 (m, 1H),2.12-1.57 (m, 13H), 1.27-1.35 (m, 2H). The relative stereochemistry ofthe two products has not unassigned.

Similarly the other compounds of Formula I can be prepared by proceedingin a similar manner as described above by simply substituting for theintermediates named in Examples 1 and 2, the other appropriateintermediates needed to make the other compounds of Formula I.

Utility Examples

EXAMPLE A Inhibitory Effect of Compounds of Formula (I) on In Vitro TNFProduction by Human Monocytes

The inhibitory effect of compounds of Formula (I) on in vitro TNFproduction by human monocytes may be determined by the protocol asdescribed in Badger et al., EPO published Application 0 411 754 A2, Feb.6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

EXAMPLE B

Two models of endotoxic shock have been utilized to determine in vivoTNF activity for the compounds of Formula (I). The protocol used inthese models is described in Badger et al., EPO published Application 0411 754 A2, Feb. 6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

The compound of Example 1 herein demonstrated a positive in vivoresponse in reducing serum levels of TNF induced by the injection ofendotoxin.

EXAMPLE C Isolation of PDE Isozymes

The phosphodiesterase inhibitory activity and selectivity of thecompounds of Formula (I) can be determined using a battery of fivedistinct PDE isozymes. The tissues used as sources of the differentisozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, guinea-pigheart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5)PDE V (also called "Ia"), canine trachealis. PDEs Ia, Ib, Ic and III arepartially purified using standard chromatographic techniques Torphy andCieslinski, Mol. Pharmacol., 37:206-214, 1990!. PDE IV is purified tokinetic homogeneity by the sequential use of anion-exchange followed byheparin-Sepharose chromatography Torphy et al., J. Biol. Chem.,267:1798-1804, 1992!.

Phosphodiesterase activity is assayed as described in the protocol ofTorphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive IC₅₀'s in the nanomolar to μM range for compounds of the workings examplesdescribed herein for Formula (I) have been demonstrated.

What is claimed is:
 1. A compound of Formula I ##STR10## wherein: R₁ is--(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) C(O)NR₄ (CR₄ R₅)_(m)R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄ R₅)_(r) R₆ wherein thealkyl moieties unsubstituted or substituted with one or more halogens;mis 0 to 2; n is 0 to 4; r is 0 to 6; R₄ and R₅ are independentlyselected hydrogen or C₁₋₂ alkyl; R₆ is hydrogen, methyl, hydroxyl, aryl,halo substituted aryl, aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃alkyl, indanyl, indenyl, C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl,furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl,tetrahydrothiopyranyl, thiopyranyl, C₃₋₆ cycloalkyl, or a C₄₋₆cycloalkyl containing one or two unsaturated bonds, wherein thecycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1to 3 methyl groups, one ethyl group, or an hydroxyl group; providedthat:a) when R₆ is hydroxyl, then m is 2; or b) when R₆ is hydroxyl,then r is 2 to 6; or c) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then m is 1 or 2; or d) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then r is 1 to 6; e) when n is 1 and m is 0, then R₆ is other than H in--(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆ ; X is YR₂, fluorine, NR₄ R₅, or formylamine; Y is O or S(O)_(m') ; m' is 0, 1,or 2; X₂ is O or NR₈ ; X₃ ishydrogen or X; X₄ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈ R₈, or NR₈R₈ ; R₂ is independently selected from --CH₃ or --CH₂ CH₃ optionallysubstituted by 1 or more halogens; s is 0 to 4; W is alkyl of 2 to 6carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbonatoms; R₃ is COOR₁₄, C(O)NR₄ R₁₄ or R₇ ; Z is OR₁₄, OR₁₅, SR₁₄, NR₁₀R₁₄, NR₁₄ C(O)R₉ ; Y' is O or S; R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkylwherein the R₁₂ or C₁₋₆ alkyl group is unsubstituted or substituted oneor more times by methyl or ethyl unsubstituted or substituted by 1-3fluorines, --Br, --Cl, --NO₂, --NR₁₀ R₁₁, --C(O)R₈, --CO₂ R₈,--O(CH₂)₂₋₄ OR₈, --O(CH₂)₂₋₄ OR₈, --O(CH₂)_(q) R₈, --CN, --C(O)NR₁₀ R₁₁,--O(CH₂)_(q) C(O)NR₁₀ R₁₁, --O(CH₂)_(q) C(O)R₉, --NR₁₀ C(O)NR₁₀ R₁₁,--NR₁₀ C(O)R₁₁, --NR₁₀ C(O)OR₉, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁,--C(NCN)NR₁₀ R₁₁, --C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁,--NR₁₀ S(O)₂ R₉, --S(O)_(m') R₉, --NR₁₀ C(O)C(O)NR₁₀ R₁₁, --NR₁₀C(O)C(O)R₁₀, or R₁₃ ; q is 0, 1, or 2; R₁₂ is R₁₃, C₃ -C₇ cycloalkyl, oran unsubstituted or substituted aryl or heteroaryl group selected fromthe group consisting of (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1-or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl,furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl; R₈ isindependently selected from hydrogen or R₉ ; R₉ is C₁₋₄ alkyl optionallysubstituted by one to three fluorines; R₁₀ is OR₈ or R₁₁ ; R₁₁ ishydrogen, or C₁₋₄ alkyl unsubstituted or substituted by one to threefluorines; or when R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may together withthe nitrogen form a 5 to 7 membered ring comprised of carbon or carbonand one or more additional heteroatoms selected from O, N, or S; R₁₃ isa substituted or unsubstituted heteroaryl group selected from the groupconsisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, and thiadiazolyl, and where R₁₃ is substituted on R₁₂ orR₁₃ the rings are connected through a carbon atom and each second R₁₃ring may be unsubstituted or substituted by one or two C₁₋₂ alkyl groupsunsubstituted or substituted on the methyl with 1 to 3 fluoro atoms; R₁₄is hydrogen or R₇ ; or when R₈ and R₁₄ are as NR₈ R₁₄ they may togetherwith the nitrogen form a 5 to 7 membered ring comprised of carbon orcarbon and one or more additional heteroatoms selected from O, N, or S;R₁₅ is C(O)R₁₄, C(O)NR₈ R₁₄, S(O)_(q) NR₈ R₁₄ or S(O)_(q) R₇ where q is0, 1 or 2; provided that:(f) R₇ is not C₁₋₄ alkyl unsubstituted orsubstituted by one to three fluorines;or the pharmaceutically acceptablesalts thereof.
 2. A compound according to claim 1 wherein R₁ is --CH₂-cyclopropyl, --CH₂ -C₅₋₆ cycloalkyl, --C₄₋₆ cycloalkyl unsubstituted orsubstituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzylor --C₁₋₂ alkyl unsubstituted or substituted by 1 or more fluorines, and--(CH₂)₂₋₄ OH; R₂ is methyl or fluoro-substituted alkyl, W is ethynyl or1,3-butadiynyl, R₃ is R₇ where R₇ is an unsubstituted or substitutedaryl or heteroaryl heteroaryl ring, and X is YR₂.
 3. A compoundaccording to claim 2 wherein R₇ is unsubstituted or substituted--(CH₂)₀₋₂ (2-, 3- or 4-pyridyl), (CH₂)₁₋₂ (2-imidazolyl), (CH₂)₂(4-morpholinyl), (CH₂)₂ (4-piperazinyl), (CH₂)₁₋₂ (2-thienyl), (CH₂)₁₋₂(4-thiazolyl), substituted or unsubstituted pyrimidinyl, orunsubstituted or substituted (CH₂)₀₋₂ phenyl.
 4. A compound according toclaim 3 which istrans-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylcyclohexan-1-ol!, orcis-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylcyclohexane-1-ol!.5. A pharmaceutical preparation comprising a compound of Formula Iaccording to claim 1 and a pharmaceutically acceptable excipient.
 6. Amethod for treating asthma which comprises administering to a mammal inneed thereof an effective amount of a compound of Formula I according toclaim 1 either alone or in admixture with a pharmaceutically acceptableexcipient.